NM_001004356.3:c.1391C>T

Variant names:

• chr4-1025223-C-T
• rs4647932
• NM_001004356.3:c.1391C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001004356.3(FGFRL1):​c.1391C>T​(p.Pro464Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0594 in 1,609,166 control chromosomes in the GnomAD database, including 3,126 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P464Q) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.049 (230 hom., cov: 34)
  • Exomes 𝑓: 0.061 (2896 hom.)
• Consequence: FGFRL1 NM_001004356.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.63
• Publications: 24 publications found

Genes affected

FGFRL1 (HGNC:3693): (fibroblast growth factor receptor like 1) The protein encoded by this gene is a member of the fibroblast growth factor receptor (FGFR) family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein would consist of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. A marked difference between this gene product and the other family members is its lack of a cytoplasmic tyrosine kinase domain. The result is a transmembrane receptor that could interact with other family members and potentially inhibit signaling. Multiple alternatively spliced transcript variants encoding the same isoform have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016242862).
• BP6: Variant 4-1025223-C-T is Benign according to our data. Variant chr4-1025223-C-T is described in ClinVar as Benign. ClinVar VariationId is 1169918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0631 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001004356.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFRL1	NM_001004356.3	MANE Select	c.1391C>T	p.Pro464Leu	missense	Exon 7 of 7	NP_001004356.1	Q8N441
	FGFRL1	NM_001004358.1		c.1391C>T	p.Pro464Leu	missense	Exon 7 of 7	NP_001004358.1	Q8N441
	FGFRL1	NM_001370296.1		c.1391C>T	p.Pro464Leu	missense	Exon 7 of 7	NP_001357225.1	Q8N441

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFRL1	ENST00000510644.6	TSL:1 MANE Select	c.1391C>T	p.Pro464Leu	missense	Exon 7 of 7	ENSP00000425025.1	Q8N441
	FGFRL1	ENST00000264748.6	TSL:1	c.1391C>T	p.Pro464Leu	missense	Exon 6 of 6	ENSP00000264748.6	Q8N441
	FGFRL1	ENST00000504138.5	TSL:1	c.1391C>T	p.Pro464Leu	missense	Exon 7 of 7	ENSP00000423091.1	Q8N441

Frequencies

GnomAD3 genomes AF: 0.0488 AC: 7425 AN: 152170 Hom.: 230 Cov.: 34

Gnomad AFR AF: 0.0175

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0663

Gnomad ASJ AF: 0.126

Gnomad EAS AF: 0.0181

Gnomad SAS AF: 0.0298

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.0646

Gnomad OTH AF: 0.0745

GnomAD2 exomes AF: 0.0534 AC: 12580 AN: 235606 AF XY: 0.0535

Gnomad AFR exome AF: 0.0153

Gnomad AMR exome AF: 0.0609

Gnomad ASJ exome AF: 0.128

Gnomad EAS exome AF: 0.0168

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0648

Gnomad OTH exome AF: 0.0736

GnomAD4 exome AF: 0.0606 AC: 88224 AN: 1456878 Hom.: 2896 Cov.: 38 AF XY: 0.0600 AC XY: 43438 AN XY: 724436

African (AFR) AF: 0.0180 AC: 600 AN: 33412

American (AMR) AF: 0.0619 AC: 2739 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.128 AC: 3322 AN: 26028

East Asian (EAS) AF: 0.0252 AC: 998 AN: 39590

South Asian (SAS) AF: 0.0300 AC: 2569 AN: 85710

European-Finnish (FIN) AF: 0.0343 AC: 1773 AN: 51712

Middle Eastern (MID) AF: 0.134 AC: 775 AN: 5764

European-Non Finnish (NFE) AF: 0.0645 AC: 71592 AN: 1110232

Other (OTH) AF: 0.0641 AC: 3856 AN: 60200

GnomAD4 genome AF: 0.0488 AC: 7426 AN: 152288 Hom.: 230 Cov.: 34 AF XY: 0.0472 AC XY: 3516 AN XY: 74462

African (AFR) AF: 0.0175 AC: 727 AN: 41560

American (AMR) AF: 0.0665 AC: 1017 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.126 AC: 436 AN: 3472

East Asian (EAS) AF: 0.0180 AC: 93 AN: 5172

South Asian (SAS) AF: 0.0296 AC: 143 AN: 4834

European-Finnish (FIN) AF: 0.0353 AC: 375 AN: 10616

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0646 AC: 4392 AN: 68012

Other (OTH) AF: 0.0751 AC: 159 AN: 2116

Alfa AF: 0.0621 Hom.: 1330

Bravo AF: 0.0501

TwinsUK AF: 0.0593 AC: 220

ALSPAC AF: 0.0620 AC: 239

ESP6500AA AF: 0.0173 AC: 76

ESP6500EA AF: 0.0673 AC: 578

ExAC AF: 0.0509 AC: 6148

Asia WGS AF: 0.0480 AC: 167 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.60
DEOGEN2	Benign	0.11	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.6
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.11
Sift	Benign	0.050	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.0	B
Vest4		0.020
MPC		0.14
ClinPred		0.0081	T
GERP RS		1.5
Varity_R		0.024
gMVP		0.22
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4647932; hg19: chr4-1019011; COSMIC: COSV53257958; COSMIC: COSV53257958;